N-(2-thiazolyl)-2-hydroxypyridine-5-sulfonamides



Patented Sept. 23, 1952 "UNITED s ATes 1 PATENT OFF-Ice:

I N-l(2-THIAZOLYL):Z-HYDROXYPYRIDINE-d.

SULEONAMIDES James smith;'-'Jr;; North Plainfield, N.- 1. as-.'-- signor to American Cyanamid Company; New York, N. Y., a corporation ofg-Mainep,

No- Drawing. Application April 16, 1949,

Serial No. 88,027

This invention relates to new sulfonamides and to intermediates for their manufacture.

,I have discoveredthat certain substituted S1111.

fonamides possess .activity against certainviral and rickettsialstrains, and may therefore become useful in the treatment of disease.

The new compounds of the presentinvention maybe represented in onelof their tautomeric forms by the following formula:

where R1 represents hydrogen or an aliphatic, aralkyl orv-uheterocyclic radical attached to the amide nitrogen atom, and- R2 representsa I thiazolyl ,or .isothiazolyl radicalaattached. to the amid-nitrogen-by a carbon" bond," and where the:.heterocyclic nucleus may ncontairnone or more "substituent radicals such as hydrogen, -al-.

kyl; arylyaralkyl, alkaryl, a.cy1,. carboxyand.

others.

The hydrogen atomof thehydroxy. pyridine radical'aswel'lzas. that attached'to the-amide nitrogenawhere R1 equals hydrogen are acidic 1 innature and'maybe replaced by simple-neu-x tralization witha cationic salt-forming radical.

sueh'salts' areof "particular Value, especially in' that-the solubility'of the compound is afiected 3 thereby, usually increased. Such salts .are .ob-.

viouslyginclu'ded within==the scope of the present invention.

The compounds of the present, invention may be prepared by several methods...v The preferred method-.:.is Jay: the hydrolysis 3 under alkaline :condawns of compounds having theiormulazs wherex is a halogenand Rr"and-- iR;2 are "as indicated above. These "intermediates "are new and hover and'- -while=---'they"posses no anti-viral activity; appear-to "he most convenient interme diates for the preparation of the active compounds b'f"th'iS-i-I1VBHti0n Theexactmethod of preparation of the new and novel intermediates-- and 'th'e' met-ho doi the "preparation "of the new and novel therapeutic agents shall be below and in the examples. e

To prepare the intermediates"ior hydrdlysisthe =preferred-'-method" involves-the condensation of an appropriate 2-'ha1'opyrid-ine'--'5-sulfonyl- 9 Claimsa. (c1. zeta-29.6

2 halide withan appropriate aminothia zo1e1inac 1 cord-ance with-the following equatio'mwherein R1 and R2 are as defined 'aboyeir Their halide aon the pyridine radical as well? 155 ethe halide r of 'the 1 su'lfonyl, radical :are preferably:-

chlorine; but bromine may :be used: if: ades'ired.

A preferred method of effecting.- theficonde sation is to bring "together the :reactants' shown in the above equation eta temperature "Wflihiflfb the range 0 to 100; '65" until the condensation:

is completed. It is preferred that the condense. sation be conducted withthereactants dissolved orsuspendedin a tertiary nitrogen base such as pyridine -or an organic solvent 7 "containing; a basic, compound .such as. sodium carbonate? or "f trimeth ylam ne as acid 7 acceptor or man ague-' y =ous medium containing. a. substance which-will" react with the hydreha'lide acid formed during the reaction and p event. it from: in rf ring;

"with the reaction: a

Obviously;. primary .or secondary amines shjould not .be used to bind-the acid termed in;the*;re-' I action,.as they. would tend vto react iwith'ithe sulfionyl-iha'lide and reduce the yield or esi ed": product. Oneormore moles excess .of. the "ter tiary nitrogen baseor lkaline substance ju ce sirable. .In' some cases sub antia ly the same result can be obtained by the use of an excess i quantity of the aminoheterocycle intermediate" as acid acceptor.

be hydrolyzed by heating "in the presenceof aloutlined k-ali, and the theraneuticallyuactive compounds are recovered after the reaction has run to comple'tion by precipitation cold dilute acida 'The hydrolysis'fiis best carried out ssolutio'n ea or "strong'ba-ses "such" as sodium hydroxide,

tasslum hydroxide and barium hydroxide. It is also possible to achieve the hydrolysis by the use of quaternary ammonium bases such as tetraethylammon-ium hydroxide, trimethylbenzylammonium hydroxide, etc., but they offer no special advantages over the above named inorganic bases.

The optimum concentration for the alkaline material is approximately 15% of the basic material but the hydrolysis can be run in any concentration over 1 N of sodium hydroxide or its equivalent in activity.

The hydrolysis best takes place in aqueous solution but the presence of inert solvents is not precluded and may offer some advantages. Aqueous pyridine mixtures are useful as solvents in this respect.

The hydrolysis proceeds at economic rates at temperatures above 90 C. and I have found that the range IOU-105 C., i. e., reflux conditions, is sufiicient for the type of hydrolysis desired. Greater rapidity of hydrolysis, of course, occurs at higher temperatures but special pressure equipment is then needed. Under reflux conditions, I have found that 16 hours are ample for economic conversion. Actually, it is preferred to continue the hydrolysis for 3 hours in order to assure adequate yields.

The-invention will now be illustrated by detailed description of the preparation of representative intermediates and active compounds in the following examples. It is understoodthat these compounds are merely cited by way of examples and the invention is not to b limited thereto. All parts are by weight unless otherwise indicated.

. Emamplel 8 grams of 2-chloropyridine-5-sulfony1 chloride is added to a cold solution of 10 g. of Z-aminothiazolein 50 cc. of dry pyridine. The temperature rises from 10 to 25 C. at once, and during 45 minutes it rises further to 35-40 C. After standing at room temperature for 12-14 hours the solution is poured into cold dilute hydrochloric acid. The final mixture is at pH 2.5-3.5. The brown precipitate of crude N-(Z-thiazolyl) -2-chloropyridine-S-sulfonamide is collectedon the filter and washed with water, then dried to give 8 g. of product. It can be purified by recrystallization from alcohol-water mixture or dimethylformamide-water mixture, using activated charcoal as a decolorizing agent. The compound when pure melts at 22 .5-226.5 C.

Example 2 Melting Product Point N-(4-mcthyl-2-thiazolyh- 2 -chloro pyridine -sulfon- C.

amide 179-180. 5 N-(4-phcnyl-2-thiazolyl) -2- chloropyridine 5 sulfonam P 203-206 N- (4,5-dimethyl-2-thiazolyl) -2- chlorop yridine -5- sulionamide 227-228 N (2-benzothiazolyl) -2-ch1or0pyridlne-5-sulfonamide 251-254 Example 3 15 parts of N- (Z-thiazolyl) -2-=chloropyridine-5- sulfonamide, prepared as in Example 1, is boiled under reflux in 100 parts of 15% sodium hy- 4 droxlde solution for 5 to 6 hours. The amber colored solution is cooled and acidified to Congo red test paper with dilute hydrochloric acid. The tan precipitate is collected on the filter, washed and dried. 12 parts of product are obtained. It is dissolved in 1,000 parts of water with the minimum amount of sodium hydroxid (alkaline to benzoazurine test paper), treated with activated charcoal and clarified. Dilute hydrochloric acid is added to precipitate the product which is filtered, washed and dried. Seven parts of N-(2- thiazolyl)-2-hydroxypyridine-5-sulfonamide are obtained, melting point 292-295 C. with decomposition.

Example 4 By the following the procedure of Example 3 with substitution of the corresponding N-substituted-Z-chloropyridine 5 sulfonamides, the following products are obtained:

In a similar fashion the intermediates and compounds of the table may be prepared:

Table Intermediate Final Product N (5 carboxy 2 thlazolyl) -2 chloropyridine 5 sulfonamide.

N (4 methyl 2 thiazolinyl) 2 chloropy'ridine 5 sulfonamide.

N (5 methyl 2 thiazolinyl) 2 lromopyridine 5 sulfonami e.

N (4,5-dimethyl-2-tliiazolinyl) 2 chloropyridine 5 sulfonamide.

N (4 benzyl 7 2 thiazolinyl) 2 chloropyridine 5 sulfonamide.

N (3 ethyl 2 thiazolinyl) 2 iodopyridine 5 sulfonamide.

N (3,5 dimethyl 4 carboxythiazolin 2 yl) 2 chloropyridine 5 sulfonamide.

N (2 thiazolinyl) 2 chloropyrldine 5 sulionamlde.

N (5 carboxy 2 thiazolyl) 2 I lidydroxypyridlne 5 sull'onam: 1 e.

N (4 methyl 2 thiazollnyl) 2 hydroxypyrldine 5 sulfonamide N 5 methyl 2 thiazolinyl) 2 hydroxypyndine 5 sulionamide N 4,5' dimethyl 2 thlazollnyl) 2 hydroxypyridine 5 sulfonamide. N (4 benzyl 2 thiazolinyl) -2 hydaoxypyridine 5 sullonam e. N (S-ethyl 2 thiazolinyl) 2 hydaoxypyrlduie 5 sulfonam e.

N (3,5 dimethyl 4 carboxythiazolin 2 yl) 2 hydroxypyridine 5 sulfonamide.

N (2 tlnazolinyl) 2 hydroxypyridine 5 sulfonamlde.

What I claim is:

1. Compounds of the group consisting of those having the formula where Z is chosen from the group consisting of halogen and hydroxyl radicals, and R. is a member of the group consisting of hydrogen, alkyl,

aralkylhydrocarbon and aryl hydrocarbon rad-a icals.

2. N-(Z-thiazolyl) -2-chloropyridine- 5 -sulfonamide.

a. N-(Z-thiazolyl) -2-hydroxypyridine 5 sul fonamide.

4. N -(4- methyl -2- thiazolyl) -2- hydroxypyrldine-S-sulfonamide.

5. N (4,5 dimethyl 2 thiazolyl) 2 bydrqxypyfidine-S-sulfonamide.

6. The method of preparing compounds of the eneral formula where R is a member of the group consisting oi! hydrogen, alkyl, aralkylhydrocarbon, and aryl hydrocarbon radicals which comprises hydrolyzing compounds of'the formula N X -SO1N -R N s where X is ahalide and R is as represented ahbve, in an aqueous alkaline solution at a temperature in the range 90-120" C.

7. Method of preparing N-(2-thiazolyD-2-vhydroxypyridine-5-sulfonamide which comprises 6 hydrolyzing N-(z-thiazolyl)-2-chloropyridine-5- sulfonamide in an aqueous alkaline solution and recovering the above mentioned product.

8. The method or preparing N-(4-methyl-2- thiazolyl) 2 hydroxypyrldine 5 sulfonamide .;which comprises hydrolyzing N-(4-methyl-2-thiazolyl) -2-ch1oropyrid ine -5- sultonamide in an aqueous alkaline solution and recovering the above mentioned product.

9. The method of preparing N-(4,5-dimethy1-2- thiazolyl) 2 hydroxypyridine 5 sulfonamide which comprises hydrolyzing N-(4,5-dimethyl-2- thiazolyl)-2-ch1oropyridine-5-sultonamide in an aqueous alkaline solution and recovering the 1.15 above mentioned product.

JAMES M. SMITH, JR.

No references cited. 

1. COMPOUNDS OF THE GROUP CONSISTING OF THOSE HAVING THE FORMULA 